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Ca2+ trapping by allosteric coupling explains species differences in TRPM2 inactivation reversibility
Adam Bartok1,2,3, László Csanády4,5,6
1Department of Biochemistry, Semmelweis University, Budapest, Hungary.
Communications Biology
|May 7, 2026
Summary
TRPM2 channel inactivation is reversible in zebrafish but irreversibly traps calcium in humans. This difference evolved due to tighter calcium binding in the human TRPM2 channel, explaining its persistent inactivated state.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Transient Receptor Potential Melastatin 2 (TRPM2) channels regulate body temperature in the hypothalamus.
- TRPM2 channels have unique, irreversible inactivation in humans, unlike other neuronal channels.
- The mechanism and evolution of this irreversible inactivation remain unknown.
Purpose of the Study:
- To investigate the mechanism and evolutionary basis of TRPM2 channel inactivation.
- To compare TRPM2 inactivation in zebrafish and humans.
- To elucidate the role of calcium binding in TRPM2 inactivation.
Main Methods:
- Electrophysiology
- Kinetic modeling
- Thermodynamic analysis
Main Results:
- Zebrafish TRPM2 (drTRPM2) inactivation is reversible upon ligand removal.
- Strong allosteric coupling exists between the extracellular inactivation gate and the cytosolic Ca2+ binding site in drTRPM2.
- Human TRPM2 (hsTRPM2) inactivation is technically reversible but requires subnanomolar Ca2+ levels due to evolved tight binding.
Conclusions:
- TRPM2 inactivation evolved distinct reversibility in vertebrates.
- Tight Ca2+ binding in the inactivated state of hsTRPM2 causes irreversible channel closure under physiological conditions.
- Understanding TRPM2 inactivation provides insights into channel gating mechanisms and evolution.
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